Nitric oxide treatment

ABSTRACT

The invention is a method and apparatus for treatment in which nitric oxide is supplied from a source to a patient for inhalation incorporating a regulator to control the flow of nitric oxide from the source to the patient, a monitoring apparatus to monitor the patient&#39;s respiration, and a controller to cause the regulator to permit the egress of a very short pulse of nitric oxide of a known, predetermined volume at a predetermined time during the patient&#39;s inhalation.

FIELD OF THE INVENTION

This invention relates to nitric oxide treatment, and concerns inparticular the use of nitric oxide in the treatment of certain lungdiseases or conditions, and in apparatus for this purpose.

BACKGROUND OF THE INVENTION

There are a number of lung diseases and conditions--suffered both byhumans and by other animals, and typified by asthma (an increasinglyprevalent and worrying problem)--in which the peripheral parts of thelung, namely those tiny airways and air spaces known respectively asbronchioles and alveoli, constrict to restrict the flow of airtherethrough. This can be extremely serious, for it is in these spacesthat oxygen in the inhaled air diffuses through the lung tissue into theblood capillaries running therethrough to bind to the haemoglobin in theblood, while carbon dioxide released by the blood diffuses out and isexhaled; obviously, if the movement of air, oxygen and carbon dioxide issignificantly reduced by this constriction the situation may become lifethreatening.

There are additionally a number of lung conditions in which the lung'ssmall peripheral arteries--the pulmonary arteries--also constrict,typically those deep in the lungs where the oxygen tension falls as inan asthmatic attack, pneumonia, or chronic lung diseases like bronchitisand emphysema (and it should also be noted that such constriction oftenoccurs without the causative mechanism being fully explained; this isthe so-called primary pulmonary hypertension). Whatever the reason, theresult is that the flow of blood to the capillaries is impaired, and theensuing increase in the resistance to blood flow--the raised pulmonaryvascular resistance--may be so severe as to cause the right ventricle ofthe heart to fail, and death to ensue.

Normally, the flow of blood to the capillaries of the lungs is closelymatched by the flow of inhaled air to the alveoli. This allows theoxygen and carbon dioxide to diffuse evenly between blood and air.However, in lung diseases like asthma, pneumonia, bronchitis andemphysema, and where there is acute injury to the lung, such as thatfollowing generalised sepsis or the inhalation of smoke and fumes, theflow of air into the alveoli no longer matches with the flow of blood tothe capillaries; air goes to parts of the lung no longer receivingblood, while elsewhere the capillaries may be receiving blood but theassociated alveoli are not receiving air. It follows that the exchangeof oxygen and carbon dioxide is impaired, possibly to the point wheredeath ensues.

The lung tissues concerned are smooth muscle, which operate, to contractor relax, and then to "set" in the state achieved. The actual activatoris chemical in nature, and it is usually possible to find, and apply,some other chemical that will either reverse the effect or block theactivator's action. Of the several ways in which the constriction of thelung airways can be treated, and the air spaces caused to open up(dilate), effectively all involve the supply to the relevant tissues'smooth muscle of a drug--a chemical--that causes the muscle to relax(and stay relaxed). The most effective treatments for asthma and likeconditions involve the inhalation as an aerosol of the chosen chemicalin normally inhaled air. However, to deal with the problem ofconstricted small pulmonary arteries only a few relieving substances areknown, and one of the most powerful--that known as prostacyclin, anextremely potent vasodilator--has to be administered on a continuousbasis by infusion into a vein and so to the pulmonary arteries.

Another well-known and effective dilating agent for treating both lungproblems of the blood-vessel-constriction type and of the asthma airwaytype is the gas nitric oxide. Nitric oxide (NO) is one of severalgaseous oxides of nitrogen commonly found in nature; two others arenitrous oxide (N₂ O), known as "laughing gas", and at one time used as ageneral anaesthetic, and nitrogen dioxide (NO₂). The latter, to whichnitric oxide is converted by a reaction with free oxygen at a rate whichis dependent on the nitric oxide concentration, is a highly reactive andrather dangerous gas that dissolves in water to form nitric acid (HNO₃)and nitric oxide, and is one of the main constituents of so-called "acidrain".

Nitric oxide is quite normally generated in animal (particularly human)life, starting from available organic nitrogenous materials or even frominorganic nitrogen derivatives (such as nitrates). For example, in thehuman system there is an enzyme called Nitric Oxide Synthase (NOS) thatdoes this, starting from the amino acid L-arginine, either continuouslyor upon induction by some other factor (the enzyme thus exists in both"constitutive" and "inducible" isoforms). Nitric oxide is rapidlyabsorbed by the lung tissue and then into the blood stream, but it isnot carried along therein because it reacts very rapidly with thehaemoglobin, the oxygen-carrying pigment in red blood cells to form thestable product methaemoglobin (and nitrite and nitrate), by which routethe nitric oxide is effectively inactivated.

Much work has been done on the metabolism of nitric oxide in the humanbody. It is known to enhance nerve conduction, to combine (bynitrosylation) with, and possibly activate, proteins, and to react withcertain superoxides to form the rather dangerous, cell-injuring,peroxynitrites. However, its main effect involves a reaction with theenzyme Soluble Guanylate Cyclase (SGC); which is found in the smoothmuscle cells of the lung airways and in the pulmonary arteries, as wellas in circulatory platelets--the cells in the blood which cause it toclot and form thrombi. In this reaction the nitric oxide activates theSGC (reacting with a haem moiety therein), and as a result there isformed a second messenger compound, cyclic Guanosine MonoPhosphate(cGMP). This cGMP is a relaxer of smooth muscle cells, and so canvasodilate blood vessels, enhancing blood flow therethrough. In theplatelet blood cell activation of SGC impedes aggregation, and thusreduces or prevents thrombosis (the undesirable clumping and clotting ofblood cells on some unsuitable surface, such as the inside of a bloodvessel such as an artery to the heart).

The effects of nitric oxide have already been used, or proposed for use,in the treatment of lung disease and conditions such as asthma,pulmonary hypertension, especially of the neonatal variety, acute lunginjury, and even chronic bronchitis and emphysema, where there is a needto dilate the small arteries or airways. It is the achievement of theseeffects which bears directly on the present invention. Morespecifically, it is the manner in which nitric oxide is administered,and the apparatus used for this administration, that concerns theinvention.

The obvious way to deliver nitric oxide to the sites in the lungs whereit is needed is by inhalation. The problem, however, is that theconcentration of nitric oxide thus delivered must be high enough to havethe required vasodilatory or bronchodilatory effect (at concentrationsof 40 ppm, nitric oxide is as effective as prostacyclin, and amounts inthe range of from 10 to 120 ppm seem generally satisfactory) and yet lowenough to minimize its rapid conversion to the harmful nitrogen dioxide(for which even as much as 5 ppm is considered a dangerous and toxicquantity). As a result, the nitric oxide concentration in the inhaledmixture with air (and sometimes with oxygen-enriched air, with itsgreater ability to oxidise the nitric oxide to the dangerous nitrogendioxide) has to be very carefully controlled; this is more difficultthan it might seem.

For most lung diseases and conditions to be treated using nitric oxide,the ideal way to administer the required mixture of gases is, with thePatient fully conscious, via a simple face mask, the mask being fedeither with the mixture itself or with the two components in controlledquantities. Unfortunately, it is all too easy for the Patient to drawadditional air in from around the edges of the mask--they never fit verywell--and so dilute the mixture to near or below the effective nitricoxide concentration (and, of course, if the amount of nitric oxidedelivered to the mask is high enough to obviate this, then it is highenough also to cause excessive nitrogen dioxide formation). Accordingly,the actually preferred mode of administration to date is via a tubeinserted right down into the Patient's lung--the process of insertion isreferred to as "intubation", the whole process of intubation andtreatment being carried out with the Patient anaesthetized--with thegases, or more suitably an appropriate preformed mixture thereof, beingfed in from a mechanical ventilator that pushes the gases in, and thenpulls them out again, in effect doing the Patient's breathing for him.Apparatus for doing this is disclosed by Dupuy et al, pp421-428 "Journalof Clinical Investigation", Vol. 90 No: 2, August 1992. Dupuy describesa system that delivers directly into the trachea a fixed concentrationof nitric oxide in air at a more or less constant rate matching thenormal breathing rate.

In either of these methods, but particularly in the latter, it isextremely desirable to keep a watchful eye on the actual amount ofnitric oxide being received deep within the lungs, and to check that thenitrogen dioxide level is below the maximum permitted value.Accordingly, each method is inevitably carried out with the assistanceof sampling and analysing equipment to detect the nitric oxide andnitrogen dioxide concentrations and to take some remedial action ifappropriate.

SUMMARY OF THE INVENTION

It is clearly desirable to find some better way of administering nitricoxide in the treatment of the sort of lung diseases and conditions towhich it is suited, and the invention seeks to put forward such animproved manner, as well as apparatus to carry it out. Morespecifically, the invention proposes a method of treatment in which thenitric oxide is administered to the Patient not continuously (either inadmixture with, or separately but side by side with a supply of, air,oxygen or oxygen-enriched air) but intermittently and in short pulses ofknown, pre-determined volume at one or more suitable time during eachinhalation. In the treatment of the constriction of the small pulmonaryarteries the very short pulse of nitric oxide is provided at the startof the inhalation, such that the resultant bolus of nitric oxide mixtureinhaled by the Patient has a nitric oxide concentration high enough tohave the desired therapeutic effect, even if admixed with someadditional air, but is of such short duration (both in time and, as aresult, in physical length) that, pushed by the following much largervolume of plain, and therefore nitric oxide-free, air/oxygen, it reachesdeeper into the lungs, where it both acts on the small pulmonaryarteries and is taken up into the capillaries to react with haemoglobin(so preventing the formation of nitrogen dioxide). By contrast, in thetreatment of asthma-like airway diseases or conditions the very shortpulse of nitric oxide is timed to fall just before the end of theinhalation. This leaves the nitric oxide in contact with the airwaysmooth muscle in sufficient concentration to cause relaxation, butbecause at the end of the inhalation the airway is flushed of all thenitric oxide by the air coming from alveoli and lung periphery, so thereis avoided prolonged exposure with the consequent risk of the formationof toxic nitrogen dioxide.

The benefits of this will be clear. Firstly, this manner ofadministration can be employed on a fully conscious Patient to whom thenitric oxide can be given by way of a simple face mask (although if thePatient has been, or has to be, intubated and mechanically ventilated,then of course the nitric oxide can be delivered to the tube downstreamof the ventilator). Secondly, because there is no possibility of thenitric oxide concentration within the lungs ever being higher than theinitial concentration in the very short pulse, and because the gas isnot present for a sufficient length of time to permit dangerousquantities of nitrogen dioxide to form, there is no need for anyinvasive and expensive nitric-oxide-concentration sampling equipment.

In operation, the proposed treatment method offers a means ofspecifically delivering a gaseous nitric oxide mixture to the parts ofthe lung where it is required and expected to act, and in effect only tothose parts. If it is to act on the small pulmonary arteries, then bylinking the very short pulse of the nitric oxide mixture to the start ofthe inhalation the mixture can first allow nitric oxide to diffuse intothe smooth muscle of the resistant arteries which are just before thecapillaries of the lungs, where nitric oxide will be taken up by thehaemoglobin and be inactivated. Little or none of the nitric oxidemixture will stay in the main airways of the lungs, where the uptake ofnitric oxide is very slow (and where oxidation to nitrogen dioxide mighttake place). By placing the nitric oxide mixture at the front of theinhaled breath the remaining gas mixture can have a high oxygen level,and the absolute amount of nitric oxide in the inspirate can be kept ata minimum. Conversely, if the very short pulse of nitric oxide mixtureis timed towards the end of the inhalation then it is alright if thenitric oxide is be left in contact just with the airways. Again, highconcentrations of oxygen can be used in the preceding breath, the oxygenwill be taken up by diffusion in the alveoli, and the exhaled air (witha high concentration of carbon dioxide) will flush the remaining nitricoxide from the lungs. In both cases the therapeutically-optimalconcentration of nitric oxide can be used, but with only a smallfraction of the breath made up of the nitric oxide mixture so there is avery substantial lessening of the chances of toxic doses being given.

With the benefit of hindsight, and such an explanation, the idea of apulsed treatment of this sort might seem to be rather obvious. Thiscannot be so, however, for nitric oxide has been used in the treatmentof lung diseases and conditions for several years, despite thewell-known problems associated with that use, and yet until now therehas been no appreciation of the benefits to be derived from a deliveryutilising very short pulses. Indeed, even though equipment for thedelivery of pulses of other gases that might be generally required bythe body--typically oxygen, as is disclosed in Puritan-Bennett WO87/06,142 (which describes an oxygen-delivery system employing a demandvalve controlled by breath-sensor-driving electronics)--seems to be wellknown, there has hitherto been no suggestion that there might be somebenefit to be derived, enabling treatment of specified parts of thelungs themselves, by delivering nitric oxide in a similar way.

In one aspect, therefore, the invention provides a method of treatment(of the human or animal body) for use in connection with lung disease orconditions of the type that can be treated by the administration ofgaseous nitric oxide by inhalation, in which:

the nitric oxide is administered to the Patient, at a concentration highenough to have the desired therapeutic effect, intermittently and invery short pulses of known, pre-determined duration either at thebeginning or towards the end of each inhalation, as appropriate to thedisease or condition to be treated;

such that in operation the nitric oxide is delivered specifically to thesite of interest in the Patient's lung.

In another aspect the invention provides nitric oxide treatmentapparatus for carrying out the treatment of a Patient with nitric oxidein connection with a lung disease or condition of the type that can betreated by the administration of gaseous nitric oxide by inhalation,which apparatus comprises:

means for supplying gaseous nitric oxide from a source thereof to thePatient for inhalation thereby, the supply means incorporating regulatormeans to control the egress of nitric oxide from the source; and

means to monitor the Patient's respiration;

which apparatus also includes means to cause the regulator means topermit the egress of a very short pulse of nitric oxide of a known,predetermined duration either at the start or towards the end of aninhalation, whereby the nitric oxide is delivered specifically to thesite of interest in the Patient's lung.

The meaning of the term "very short" is discussed in more detailhereinafter.

If the nitric oxide is administered at the beginning of the inhalation,the resultant bolus of inhaled nitric oxide mixture reaches the deeperparts of the lungs to act before being absorbed therein, and before anysignificant amount of nitrogen dioxide occurs, while if administeredtoward the end of the inhalation the bolus just reaches the airwaysonly, where it can cause relaxation of any airways constriction beforebeing flushed from the lungs by the exhaled gases.

The invention involves the administration of nitric oxide from a sourcethereof. Most conveniently, and to facilitate the dispensing of a small,known volume, the nitric oxide is in heavily diluted admixture with aninert carrier, typically nitrogen. A convenient actual source, then, isa cylinder of nitric oxide/nitrogen mixture under pressure, a typicalmixture containing as little as 100 ppm nitric oxide in nitrogen down toas low as 10 ppm, conveniently about 40 ppm. As the regulator valve iscracked open so the cylinder pressure drops and some of the mixtureexpands out of the cylinder, to be delivered to the Patient.

The normal maximum flow rate for the nitric oxide (or, preferably, forthe nitrogen-diluted nitric oxide)--that is, the flow rate from thesource obtained when the regulator valve is in its normal openposition--is chosen to provide a pulse of the required very shortduration (as is explained further hereinafter) that neverthelesscontains a therapeutically-suitable amount of the nitric oxide. Ingeneral, a suitable nitric oxide flow rate can be chosen from a widerange of values, but typically the real nitric oxide flow rate will bearound a few millilitres (at NTP, normal temperature and pressure) perminute. Thus, for a nitric oxide source in the form of a 100 ppm nitricoxide/nitrogen mixture the mixture flow rate will be in the units or lowtens of litres a minute--say, in the range 5 to 50 l/min, typically 12l/min.

Of course, because in operation the nitric oxide, already preferablyadmixed with a carrier such as nitrogen, is--as discussedhereinafter--further conjoined with air, oxygen or oxygen-enriched airimmediately prior to its administration to the Patient, the actualoverall flow rate of the gas as it is carried into the lungs may besomewhat different from the flow rate of the nitric oxide/nitrogenadmixture released from the source. However, the point of the use of apulse of nitric oxide admixture is that what actually goes into thePatient's airways is a bolus of nitric oxide/nitrogen relatively free ofany air/oxygen administered in parallel therewith; it will be understoodthat what is important is the concentration of the nitric oxide in thisbolus, coupled with the physical length thereof (which latter is ofcourse determined primarily by the duration of the very short pulse).

The nitric oxide is administered--that is, it is fed--to the Patient.This administration may take any appropriate form. For example, wherethe Patient is conscious, and breathing through a mask, the nitric oxidemay be delivered along a pipe to the mask, where it is automaticallyinserted into the air/oxygen also supplied to the mask, the resultingcombination being then inhaled by the Patient. Alternatively, where thePatient is unconscious, and is intubated and on a ventilator, then thenitric oxide delivery may again be along a pipe but now into thedelivery tube from the ventilator just before it enters the Patient'sairways.

In the invention the nitric oxide is taken from a source thereof viaregulator means to control the egress of nitric oxide from the source.The regulator is in essence simply a valve that can be opened and shut,conveniently by an electrically-operated solenoid arrangement, to permita very short pulse, or very small amount, of nitric oxide to leave thesource and pass along to the Patient. There are many standard regulatorssuitable for this type of operation; they need no further comment here.

The nitric oxide is administered to the Patient either together with,or--and preferably--separately but side by side with, a supply of air,oxygen or oxygen-enriched air. This is in itself quite conventional, andneeds no further comment here, except perhaps to observe again that thevery short pulse method of the invention makes it easier and safer tosupply the Patient with high concentrations of oxygen, and still avoidthe formation of nitrogen dioxide.

In the invention the nitric oxide is fed to the Patient intermittentlyand in very short pulses of known, pre-determined volume either at thebeginning or towards the end of each inhalation. In this context"intermittently" means, for the most part, once each breath; it is,however, more difficult to give a precise meaning to the term "veryshort", though for general guidance the following comments may be ofassistance. The term "very short" means primarily that the provision ofsufficient nitric oxide for each bolus thereof is achieved by supplyingthe gas for a time period--of the order of a few tens ofmilliseconds--that is very short compared with the length of an averageinhalation (which is about 1.5 second). However, there is more to theshortness of the pulse than just its temporal duration, for, the purposeof the pulse being to provide a bolus of nitric oxide both of relativelyhigh concentration and of relatively short physical length, both theactual flow rate of the nitric oxide (perhaps in its carrier mixtureform) as it is fed to the Patient and also the actual concentration ofthe nitric oxide in that fed gas are important factors. What has beendetermined by experiment is that for nitric oxide flow rates of the sortdiscussed hereinbefore--actual nitric oxide rates of a few millilitres(from 1 to 4, say) per minute, or 100 ppm nitric oxide/nitrogen mixturerates of the low tens of litres per minute (typically 12 l/min)--verysatisfactory results are obtained using pulse durations of a few tens ofmilliseconds, and typically 20 to 30 msec. Thus, while it will clearlybe understood that what is a "very short" pulse depends upon the flowrate and concentration of the administered nitric oxide, nevertheless itcan now be said that the term "very short" means "of the order of a fewunits or tens of milliseconds". Or, to put it another way, the termmeans roughly one thousandth of the length of an average inhalation.

The nitric oxide pulse is delivered either at the beginning or towardsthe end of each inhalation. For the treatment of constriction of thesmall pulmonary blood vessels the pulse of nitric oxide is timed tooccur at the beginning of the inhalation. This pulse is then pushed intothe lungs by the subsequent air (or oxygen or air/oxygen). The nitricoxide then penetrates the deeper parts of the lungs, before significantoxidation to nitrogen dioxide, to be absorbed by haemoglobin in theblood. On the other hand, for the treatment of asthma-like diseases thepulse of nitric oxide is timed towards the end of the inhalation, sothat for the short time before the following exhalation starts thenitric oxide is only in contact with the airways, and that for only abrief period before it is flushed from the lungs by the exhaled air.

To trigger the nitric oxide pulse (at the beginning or near the end ofeach inhalation), the invention incorporates means to detect this start(or, alternatively, to detect the end of the immediately-precedingexhalation), and then to cause the regulator means to permit the egressof the desired very short pulse at the appropriate time. Actuallydetecting the start of an inhalation is comparatively simple, and couldbe effected by a conventional mechanical pressure-drop responsivearrangement such as the demand valve employed in an aqualung or otherunderwater breathing apparatus. However, to control not merely theopening of the regulator but also its subsequent closing after apredetermined time requires a little more, and conveniently there isused an electronic system that includes a pressure or other appropriatesensor operatively connected to a small computing device that can beprogrammed to output to the regulator the appropriate control signals asneeded. The sensor can be carried in the Patient's mask, or in the tubeinto his airways (if his breathing is being mechanically assisted), orin the exhalation port; it can be arranged to detect air flow, using aconventional thermistor arrangement, or--and preferably--to detectdirectly an actual pressure change (a rise or drop, as appropriate).

Just as the invention will involve the use of any convenient means forsupplying the Patient with air, oxygen or oxygen-enriched air to beinhaled mixed with the nitric oxide, so it will as appropriate utilisesome suitable face mask, intubation tube, and/or ventilator. None ofthese need any further comment at this time.

BRIEF DESCRIPTION OF THE DRAWINGS

An embodiment of the invention is now described, though by way ofillustration only, with reference both to the Tests describedhereinafter and to the accompanying Drawings in which:

FIG. 1 shows a Patient being treated with nitric oxide according to theinvention;

FIG. 2 shows a bolus of nitric oxide/air mixture travelling down deepinto the Patient's lungs;

FIG. 3 shows graphically the Patient's respiration, and the timing ofthe nitric oxide pulses at the start of an inhalation; and

FIG. 4 is a black box schematic of apparatus according to the inventionused for providing Test Data relating to the treatment method of theinvention;

FIG. 5 shows the physical nature of some of the FIG. 4 apparatus;

FIGS. 6A/b show graphically values relating to the initial calibrationof the FIG. 4 apparatus; and

FIGS. 7A/B show graphically some of the results achieved using the FIG.4 apparatus.

DETAILED DESCRIPTION OF THE INVENTION

The apparatus shown in use in FIG. 1 is very simple. It comprises a facemask (11) to which an oxygen-enriched air mixture is fed along a firsttube (12: from a source not shown) and a nitric oxide/nitrogen mixture(NO/N₂) is fed along a second tube (13) from a cylinder (15) thereof.The nitric oxide supply is controlled by a regulator (16) which itselfis controlled by a suitably programmed box of electronics (17) driven bysignals obtained from a sensor (18) in the mask 11 (the sensor is athermistor that is cooled by, and so detects, airflow). In thisparticular case the system is arranged to note the end of an exhalation,and to trigger the operation of the regulator 16 so as to have the pulseof nitric oxide fed into the mask ready for the beginning of the nextinhalation.

FIG. 2 shows the progress of a bolus (21) of nitric oxide/air mixturedown the Patient's windpipe (22) and on deep into his lungs (23). Thoughat first sight it looks as though there are several bolus preceding oneafter the other, in fact there is only one, shown at different times onits journey, and the object of the Figure is to show how the bolusremains as an entity, and does not disperse as it progresses (and soreaches the deepest part of the lungs as a concentrated burst of nitricoxide with the full therapeutic effect required).

The timing of the bolus delivery is shown graphically in FIG. 3. Airflowin and out of the lungs takes place at regular intervals, as the Patientbreathes, and just as the flow starts a pulse of nitric oxide isdelivered, and "washed down" with the remaining inhaled air.

The nitric oxide spike delivery system shown in FIGS. 4 and 5 involvesrespectively a valve operating system (shown in FIG. 4) and a cylindercontaining 100 ppm nitric oxide in a carrier gas diluent such asnitrogen and having a two-stage regulator (FIG. 5). The regulator, whichmay be of any conventional design, drops the pressure of the 100 ppmnitric oxide/nitrogen mixture so that with a valve-open flow rate of 12litres per minute opening the valve for 0.5 seconds causes a volume of100 cc to be delivered. After the main pressure reducing regulator, itis the valve orifice that offers the greatest resistance to flow;therefore it is possible to specify the flow rate from the inletpressure delivered to this valve. FIG. 5 also shows joined to the valveand cylinder the calibration study equipment; this is used to measurethe volume of gas mixture emitted from the valve with various openingtimes. The results of this study are shown in FIGS. 6A/B, and arediscussed below (the actual volumes obtained are there compared with thevolumes expected on the basis of the valve having a "square wave"opening form).

Valve operation may be triggered either manually via an externalpressure pad switch or automatically. The manual switch acts on theswitch shown in FIG. 4, triggering a pulse of predetermined width whichthen acts on the drive of the valve. The automatic trigger issynchronised to the airway pressure signal shown also in FIG. 4. Oncetriggered, the period that the valve is open is specifiedelectronically.

A trigger output signal is available from the gas switch unit so thatthe instant that the nitric oxide spike is delivered during therespiration cycle can be monitored and recorded on the data acquisitionsystem.

Where necessary, signals have been optically isolated to avoidcircumvention of the physiological monitoring system electricalisolation barrier.

The actual gas valve switch used in the apparatus has been designedspecifically for use in the operating theatre, and accordingly is housedin a fully sealed box (shown by the dashed outline) to prevent theingress of fluids and permit easy cleaning. The unit operates from asingle PP3 style 9 V battery down to a level of 6 V (a low batteryindicator is provided).

The valve utilised is a 1.6 mm orifice miniature solenoid valve withstainless steel base block, tube and plunger assembly, and is fittedwith an EPDM seal (all of these are as recommended for use with nitricoxide). The coil is operated from a 6 V direct current supply, and has apower rating of 5 watts. Minimum operating time is 10 ms.

In order to maximise battery life, the valve coil is energised at a peakcurrent of 400 mA for 7.5 ms, and then the current is reduced to aholding level of 100 mA for the remaining period that the valve ismaintained open. Constant current drive is employed to exploit the fulldischarge range of the battery. A minimum of one thousand operationswith a pulse width of 625 ms should be possible from a high performanceAlkaline Manganese (i.e. Duracell PROCELL) battery.

The valve-open time may be set to one of twelve intervals in the rangeof 10 mS to 2 s. An LED is provided to indicate the state of the valve.The system may be manually triggered from a pneumatic pressure padswitch which permits easy operation either by hand or foot.Alternatively, triggering can be performed automatically, as describedbelow.

In its automatic mode the apparatus includes an automatic trigger thatis fed a suitable trigger stimulus derived from the repeated airwaypressure output of the physiological pressure monitoring system. Therepeated output is an amplified and stabilised version of the sensorsignal. However, to ensure reliable detection of a respiratory event (inthe Tests described hereinafter, this is the onset of expiration) somefurther signal conditioning is required. This latter takes the form of asecond-order low pass filter (to remove mains interference), zero-offsetcancellation, and amplification. The expiration event is then used toinitiate a delayed time interval which, once this has elapsed, generatesa trigger pulse to the gas valve switch. The delay time is adjustable inthe range of 0 to 5 seconds, enabling the automatic trigger to bepositioned at any desired point in the respiration cycle. This unitderives its operating power from the +12 V and-12 V rails of the dataacquisition system.

In the physiological studies described below the valve assembly wasconnected to the intratracheal tube use to ventilate the test animalwith a Manley Mechanical ventilator. Airway pressure was measured by anair-filled transducer (Spectromed P20, Coventry, UK). The valve wastriggered by a fall in the airway pressure on expiration. The switchprovided a burst of 100 ppm nitric oxide/nitrogen gas mixture at thestart of the inhalation (the start was judged from direct observation ofthe pressure wave form and an electrical signal from the valve).

By way of contrasting the invention's treatment against thatconventionally used in the field, the effects of different times ofopening of the switch according to the invention were compared with thesituation and results obtaining when the whole of the inhaled volumebeing made up of nitric oxide in air at a concentration of 40 ppm.

TEST RESULTS Studies

(1) Calibration of the valve

The first study was to determine the volume of gas delivered by thecylinder/valve assembly used in the FIG. 1 apparatus of the invention.This was measured spirometrically; as shown in FIG. 5, a measurementdevice was constructed to measure the volume displaced from a "floatingbell" on a water container. The volume displaced by a series of opentimes of the valve (from 10 ms to 1 sec) are shown graphically in FIGS.6A & B (6B shows the 10 to 100 ms range at a larger scale), togetherwith the calculated (expected) volumes delivered by the valve if itoperated with total efficiency (i.e. it opened with a "square wave"form). The observed volumes were used to provide the amount of gaseousnitric oxide delivered to the ventilation system in the actual Testexperiments discussed further below.

2) The Physiological Studies

Animal Preparation

The experiments providing the desired Test Results were carried out onpigs which weighed between 35 and 60 kg (mean: 45.2 kg).

The animals were obtained from a commercial breeding centre, and werepathogen-free. They were initially sedated with 0.5 mg/kg Droperidol(DROPLEPTAN, from Janssen Pharmaceutical Ltd, Oxon, UK) and 0.3 mg/kgMidazolam (HYPNOVEL, from Roche, Welwyn, UK). A 19-21 gauge intravenouscannula was placed in a peripheral vein of their ear, and sodiumpentobarbital (SAGATAL, from Rhone-Polenc, UK) was infused in (at a doseof up to 15 mg/kg) to induce anaesthesia. The infusion was maintained at9-11 ml/hr up to a maximum of 30 mg/kg. The animal was then intubatedthrough a tracheotomy, and then paralysed with 0.2 mg/kg Alcuronium(ALLOFERIN, from Roche, Welwyn, UK). The ventilator was run at a tidalvolume of 500 ml and 15 breaths per minute, and air was used.

The left carotid or femoral artery was cannulated in order to measuresystemic arterial pressure. The adequacy of anaesthesia was assessed bymonitoring the responses of the heart rate and systemic blood pressureto noxious stimuli.

Access to the thoracic organs was achieved by a midline sternotomy. Thepericardium was opened and 1,000 U/kg Heparin (from Paynes & Byrne,Greenford, UK) was administered into the right atrium. Two cannulae (ID5 mm, from Portex, UK) were placed respectively in the inferior venacava and in the right ventricle through an incision in the right atrium.The animal was exsanguinated via the cannula in the inferior vena cavawhile 1-2 l of buffered Krebs-Ringers solution containing 40 gm/lDextran 70 were concurrently infused into the right ventricle. The rateof infusion was adjusted to keep the systemic arterial blood pressurestable until 3 litres of blood were obtained.

The heart was then stopped by an intracoronary injection of 10⁻³potassium chloride, and a stiff cannula (ID 13 mm) was placed in themain pulmonary artery. Through an incision in the left ventricle,another cannula (ID 16 mm) was retrogradely inserted into the leftatrium and secured by heavy silk ties which prevented ballooning of theatrial appendage. The cannulae were then connected to an externalperfusion system. Time from cardiac arrest to the start of perfusion wasnever more than 20 minutes.

The perfusion circuit used a heated jacketed reservoir which receivedautologous blood from the left atrium. From the reservoir, the perfusatewas pumped into the pulmonary artery by means of a roller pump (WatsonMarlow Model 5001R, UK). A 150 ml reservoir with a small cushion of airwas interposed between the pump and the arterial cannula; this acted asa pulse damper as well as a bubble trap. Perfusate temperature wasmonitored with a thermistor in the inflow cannula. The height of thevenous reservoir could be adjusted to the desired venous pressure.Perfusion was instituted at 10 ml/min/kg, and slowly increased by 10ml/min/kg steps over an hour until a flow rate of 100 ml/min/kg wasreached.

The variables recorded throughout the experiments were cardiac output(pulmonary blood flow) (Q), pulmonary artery pressure (PAP), left atrialpressure (PWP), systemic arterial pressure (SAP), and central venouspressure (CVP). The pulmonary vascular resistance (PVR) was calculatedfrom Q/(PAP-PWP). For the purposes of analysis the analogue outputs ofthe transducers and ultra-sonic flow metres and, where required, thenitric oxide analyser were sampled on demand by a personal computer(Macintosh SE 30, Apple Computer Inc., Cupertino, Calif., USA) using a16 bit ADC interface at a sample rate of 500 Hz (MP100, Biopac System,Inc., Goleta, Calif., USA).

Protocols

(a) Inhibition of endogenous Nitric Oxide Synthase (NOS) of the Lungs

The inhibition of vascular endothelial NOS was achieved by adding to theperfusion solution the analogue for L-Arginine called N^(G)-nitro-L-arginine methyl ester (L-NAME) (at a rate of 1-2 mg/kg). Thiscauses a rise in both PVR and the systemic vascular resistance (SVR).

(b) Infusion of Thromboxane Analogue

The constrictor was an analogue of Thromboxane called U46619; 10pmol/min was infused to elevate the PVR some twofold.

(c) Delivery of the Spike of nitric oxide

In the first protocol the nitric oxide/nitrogen cylinder contained 40ppm. The valve was activated to give in random order (10, 20, 40, 80,160, 320, 640 and 1000 ms) from the start of the breath. There were fourmeasurements of the PVR over five minutes, and a total of five pigs werestudied.

In the second protocol a period of ventilation of the lungs with 40 ppmof nitric oxide in air was compared with the spike. The spike was set atdifferent times of opening of the valve (10, 80, 160 and 320 ms) and thenitric oxide source was a cylinder of 100 ppm of nitric oxide/nitrogen.

Results

Protocol (a)

As can be seen from the results shown graphically in FIG. 7A, thepulmonary vascular resistance (PVR) is raised using L-NAME at time 0.Then, with nitric oxide/nitrogen pulses, or spikes, of duration varyingfrom 1 sec down through 240, 120, 80, 40, 20 to 10 msec, it can be seenhow the PVR fell to a level below baseline (the zero line). The resultsshow the mean values and the standard deviation. It will be seen thatthe 10 msec burst of nitric oxide/nitrogen was just as effective as the1 sec burst.

Protocol (b)

In FIG. 7B the PVR value after administration of U46619 is shown as100%. The percentage fall in PVR with "spikes" of nitric oxide/nitrogenis compared with continuously-inhaled nitric oxide (shown as C). Thecontrol full breath is of nitric oxide at 40 ppm in air whiles thebursts are 100 ppm. Here it can be seen that 10 msec of 10 ppm nitricoxide/nitrogen is as effective as 40 ppm of nitric oxide/air throughoutthe entire inhalation (ie, as long as one to two seconds).

Conclusion

In the pig lungs where the pulmonary vascular resistance (PVR) iselevated with U46619 and the NOS inhibitor, spiked nitric oxide is aseffective as 1 sec or continuous full inhalation of nitric oxide inreducing the PVR. In other words, as little as a 10 ms burst of nitricoxide is equivalent to a whole breath of nitric oxide.

It can be calculated that spiked 0.74 ppm nitric oxide can give the sameeffect as 40 ppm in the whole breath. Thus, toxicity risk is lessened,there is no need for complex gas mixing, and potentially any breathingpattern can be used.

I claim:
 1. An apparatus for carrying out the treatment of a patientwith nitric oxide in connection with one of a lung disease or conditionof the type that can be treated by the administration of gaseous nitricoxide by inhalation, the apparatus comprising:means for supplyinggaseous nitric oxide from a source thereof to the patient substantiallyfree of any respiratory gas for inhalation thereby, the supply meansincorporating regulator means to control the egress of nitric oxide fromthe source; means to monitor the patient's respiration; and controlmeans for controlling the regulator to cause the egress from the sourceof a very short pulse of nitric oxide of a known, predetermined durationat a predetermined instant during an inhalation, the pulse having aduration less than a duration of the inhalation, whereby the nitricoxide is delivered specifically to the site of interest in the patient'slung.
 2. An apparatus as claimed in claim 1 which includes the nitricoxide source wherein the nitric oxide is in admixture with an inert gas.3. An apparatus as set forth in claim 2 wherein the source is acontainer of nitric oxide/nitrogen mixture under pressure, and containsfrom 100 ppm to 10 ppm nitric oxide in nitrogen.
 4. An apparatus asclaimed in claim 1 further comprising:a face mask; and a pipe coupledbetween the source and the face mask for providing the nitric oxide tothe patient.
 5. An apparatus as claimed in claim 1 wherein the nitricoxide is fed to the patient in pulses of from 5 to 50 millisecondduration.
 6. An apparatus as claimed in claim 1 wherein the patient'srespiration comprises a series of inhalations and exhalations and thecontrol means controls the regulator means to permit the egress of thevery short pulse of nitric acid at the start of each inhalation.
 7. Anapparatus as claimed in claim 6 wherein the means to monitor detects airpressure changes in the patient's respiration.
 8. An apparatus asclaimed in claim 1 wherein the patient's respiration comprises a seriesof inhalations and exhalations and the control means controls theregulator means to permit the egress of the very short pulse of nitricacid towards the end of each inhalation.
 9. A method for treatment of apatient with nitric oxide in connection with a condition of the typethat can be treated by the administration of gaseous nitric oxide byinhalation, the method comprising the steps of:monitoring the patient'srespiration; administering nitric oxide to the patient at aconcentration sufficient to have a desired therapeutic effectintermittently and in very short pulses of known, predetermined durationless than a duration of the patient's respiration and substantially freeof any respiratory gas at a specified instant in the patient'srespiration as appropriate to treat the condition.
 10. A method as setforth in claim 9 wherein the respiration comprises a series ofinhalations and exhalations and wherein the instant is at the beginningof each inhalation.
 11. A method as set forth in claim 9 wherein therespiration comprises a series of inhalations and exhalations andwherein the instant is towards the end of each inhalation.
 12. A methodas set forth in claim 9 wherein the nitric oxide is in an admixture withan inert carrier.
 13. A method as set forth in claim 12 wherein thenitric oxide is in an admixture with nitrogen in a concentration of 100ppm to 10 ppm nitric oxide to nitrogen.
 14. A method as set forth inclaim 13 wherein the very short pulses are 5 to 50 milliseconds induration.
 15. An apparatus for treatment of a patient with nitric oxidecomprising:a source of gaseous nitric oxide; a regulator coupled to thesource to control the flow of the nitric oxide from the source to thepatient; a monitor for monitoring the patient's respiration; and controlmeans responsive to the monitor for controlling the regulator to causethe flow from the source of a very short pulse of nitric oxide of aknown, predetermined duration less than a duration of the patient'srespiration and at a predetermined instant during the patient'srespiration, whereby the nitric oxide is delivered specifically to thesite of interest in the patient's lung substantially free of anyrespiratory gas.
 16. An apparatus as set forth in claim 15 wherein thenitric oxide is in admixture with an inert gas.
 17. An apparatus as setforth in claim 16 wherein the nitric oxide is in an admixture withnitrogen in a concentration of 100 ppm to 10 ppm nitric oxide tonitrogen.
 18. An apparatus as set forth in claim 15 further comprising:aface mask; and a pipe coupled between the source and the face mask forproviding the nitric oxide to the patient.
 19. An apparatus as set forthin claim 15 wherein the very short pulse is from 5 to 50 milliseconds induration.
 20. An apparatus as set forth in claim 15 wherein thepatient's respiration comprises a series of inhalations and exhalationsand the control means controls the regulator means to permit the egressof the very short pulse of nitric acid at the start of an inhalation.21. An apparatus as claimed in claim 15 wherein the patient'srespiration comprises a series of inhalations and exhalations and thecontrol means controls the regulator means to permit the egress of thevery short pulse of nitric acid towards the end of each inhalation. 22.An apparatus as claimed in claim 15 wherein the monitor detects airpressure changes in the patient's respiration.